Signaling by cell surface death receptors: Alterations in head and neck cancer
Brandon C Leonard1, Daniel E Johnson1
1Department of Otolaryngology - Head and Neck Surgery, University of California at San Francisco, San Francisco, CA, USA.
Abstract:
Cell surface death receptors are members of the tumor necrosis factor receptor (TNFR) superfamily and mediate signals leading to the induction of apoptosis or necroptosis, as well as NF-κB-mediated cell survival. These biochemical processes play key roles in cell growth, development, tissue homeostasis, and immune responses. The downstream signaling complexes activated by different death receptors can differ significantly and are subject to multiple, distinct regulatory mechanisms. Dysregulation of signaling by the TNFR superfamily contributes to a variety of pathologic conditions, including defective immune responses and cancer. Caspase-8 signaling is important for mediating death receptor signals leading to either apoptosis or NF-κB activation. By contrast, inactivation of caspase-8 or loss of caspase-8 expression shifts death receptor signaling to the necroptosis pathway. Notably, the gene encoding caspase-8 is mutated in roughly ten percent of head and neck cancers. These findings support the hypothesis that alterations in the biochemical pathways mediated by death receptors have important consequences for the development of head and neck, and possibly other, cancers.
Insights
Cell surface death receptors regulate cell death and survival pathways. Mutations in caspase-8, crucial for these signals, are linked to head and neck cancers, suggesting a role in cancer development.
Area of Science:
- Biochemistry
- Molecular Biology
- Immunology
Background:
- Cell surface death receptors, part of the tumor necrosis factor receptor (TNFR) superfamily, control apoptosis, necroptosis, and NF-κB-mediated cell survival.
- These receptors are vital for cell growth, development, tissue homeostasis, and immune responses.
- Dysregulation of TNFR superfamily signaling is implicated in immune disorders and cancer.
Purpose of the Study:
- To investigate the role of caspase-8 signaling in death receptor-mediated pathways.
- To explore the connection between alterations in death receptor signaling and cancer development, particularly head and neck cancers.
Main Methods:
- Analysis of downstream signaling complexes activated by death receptors.
- Investigation of regulatory mechanisms governing these pathways.
- Examination of caspase-8 function in apoptosis, necroptosis, and NF-κB activation.
Main Results:
- Caspase-8 signaling mediates death receptor-induced apoptosis or NF-κB activation.
- Loss or inactivation of caspase-8 redirects death receptor signaling towards necroptosis.
- Approximately 10% of head and neck cancers exhibit mutations in the caspase-8 gene.
Conclusions:
- Alterations in death receptor signaling pathways, particularly involving caspase-8, have significant implications for cancer development.
- The findings support a hypothesis linking dysregulated death receptor signaling to head and neck cancers and potentially other malignancies.
More Related Videos
Related Concept Videos
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
01:17The Extrinsic Apoptotic Pathway
01:30Apoptosis
03:14Notch Signaling Pathway
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not...
01:15Receptor Downregulation in MVBs
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
01:21Cell-surface Signaling